Plasmodium falciparum: Three amino acid changes in the dihydrofolate reductase of a pyrimethamine-resistant mutant

Chemotherapy remains the kernel of malaria control and the available antimalarial drugs are not only expensive but also parade heterogeneous levels of toxicity and may invoke poor compliance in patients. The present study focuses on the screening of quinolone compounds against Plasmodium falciparum dihydrofolate reductase (pfDHFR) for anti-malarial potential using Glide (Schrodinger maestro 2017-1). Computational tool using Glide was employed to investigate the therapeutic relevance of six (6) quinolone derivatives retrieved from PUBCHEM via molecular docking against pfDHFR retrieved from protein data base. The results showed that, Lascufloxacin and moxifloxacin bind with higher affinity and lower free energy with catalytic domain of pfDHFR with glide score of -6.597 and -5.653 respectively compared to standard ligand (quinine) with glide score of -3.728. Lascufloxacin interacted with amino acid residue of the catalytic domain (SER 511, ARG 510, GLU 382) as evaluated by energy decomposition per residue lascufloxacin-pfDHFRcomplex. The results from this investigation, thus proposed quinolone derivatives as hit lead drug candidates which may be consider as potential inhibitor of pfDHFR.

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Faculty Opinions recommendation of Molecular modeling of wild-type and antifolate resistant mutant Plasmodium falciparum DHFR.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009237.121607 ◽

2002 ◽

Author(s):

Vivian Cody

Keyword(s):

Plasmodium Falciparum ◽

Molecular Modeling ◽

Resistant Mutant ◽

Wild Type

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Faculty Opinions recommendation of Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033087.374688 ◽

2006 ◽

Author(s):

Paul Roepe

Keyword(s):

Plasmodium Falciparum ◽

Amino Acid ◽

Proteolytic Enzyme ◽

Enzyme Systems

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Characterization and amino acid sequence of Neisseria gonorrhoeae dihydrofolate reductase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)71353-0 ◽

1984 ◽

Vol 259 (19) ◽

pp. 12291-12298 ◽

Cited By ~ 1

Author(s):

D P Baccanari ◽

R L Tansik ◽

S J Paterson ◽

D Stone

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Neisseria Gonorrhoeae ◽

Dihydrofolate Reductase

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Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.1.164 ◽

1998 ◽

Vol 42 (1) ◽

pp. 164-169 ◽

Cited By ~ 65

Author(s):

A. Nzila-Mounda ◽

E. K. Mberu ◽

C. H. Sibley ◽

C. V. Plowe ◽

P. A. Winstanley ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Dihydrofolate Reductase ◽

Drug Response ◽

Point Mutations ◽

Distinct Group ◽

Wild Type ◽

Field Isolates ◽

Vitro Data ◽

In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

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Cysteine-Free Proteins in the Immunobiology of Arthropod-Borne Diseases

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/171537 ◽

2010 ◽

Vol 2010 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

J. Santiago Mejia ◽

Erik N. Arthun ◽

Richard G. Titus

Keyword(s):

Plasmodium Falciparum ◽

Amino Acid ◽

Distribution Patterns ◽

Structural Features ◽

Structure And Function ◽

Cysteine Residues ◽

Distribution Analysis ◽

And Function ◽

Abundance And Distribution ◽

Host Parasite

One approach to identify epitopes that could be used in the design of vaccines to control several arthropod-borne diseases simultaneously is to look for common structural features in the secretome of the pathogens that cause them. Using a novel bioinformatics technique, cysteine-abundance and distribution analysis, we found that many different proteins secreted by several arthropod-borne pathogens, includingPlasmodium falciparum, Borrelia burgdorferi, and eight species of Proteobacteria, are devoid of cysteine residues. The identification of three cysteine-abundance and distribution patterns in several families of proteins secreted by pathogenic and nonpathogenic Proteobacteria, and not found when the amino acid analyzed was tryptophan, provides evidence of forces restricting the content of cysteine residues in microbial proteins during evolution. We discuss these findings in the context of protein structure and function, antigenicity and immunogenicity, and host-parasite relationships.

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